Dopamine D4 receptors belong to the dopamine D2 subfamily of receptors, which is considered to be responsible for the antipsychotic effects of neuroleptics. The characteristic extrapyramidal side effects of neuroleptic drugs, which primarily exert their effect via antagonism of D2 receptors, are known to be due to D2 receptor antagonism in the striatal regions of the brain. However, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D4 than D2 receptors and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507-526, and Sanner Exp. Opin. Ther. Patents 1998, 8, 383-393).
A number of D4 ligands, which are postulated to be selective D4 receptor antagonists, (L-745,879 and U-101958), have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194-200). However, recently it has been reported that these compounds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a silent antagonist (Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).
Consequently, D4 ligands, which are partial D4 receptor agonists or antagonists, may have beneficial effects against psychoses.
Dopamine D4 antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78-84).
Furthermore, evidence for a genetic association between the “primarily inattentive” subtype of attention deficit hyperactivity disorder and a tandem duplication polymorphism in the gene encoding the dopamine D4 receptor has been published (McCracken et al. Mol. Psychiat. 2000, 5, 531-536). A link between the D4 receptor and attention deficit hyperactivity disorder is further strengthen by published data showing that D4 receptor antagonists counteract the hyperactivity in rats induced by neonatal 6-hydroxydopamine lesions, a preclinical model for this disease (Zhang et al. Psychopharmacology 2002, 161, 100-106). This clearly indicates a link between the dopamine D4 receptor and attention deficit hyperactivity disorder, and ligands affecting this receptor may be useful for the treatment of this particular disorder.
Various effects are known with respect to compounds, which are ligands at the different serotonin receptor subtypes. As regards the 5-HT2A receptor, which was previously referred to as the 5-HT2 receptor, the following effects have been reported e.g.:
Antidepressive effect and improvement of the sleep quality (Meert et al. Drug. Dev. Res. 1989, 18, 119.), reduction of the negative symptoms of schizophrenia and of extrapyramidal side-effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders British J. Psychiatry 1989, 155 (suppl. 5), 33). Furthermore, selective 5-HT2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; “Migraine—Current trends in research and treatment”; PJB Publications Ltd.; May 1991) and in the treatment of anxiety (Colpart et al. Psychopharmacology 1985, 86, 303-305 and Perregaard et al. Current Opinion in Therapeutic Patents 1993, 1, 101-128).
Some clinical studies implicate the 5-HT2 receptor subtype in aggressive behaviour. Furthermore, a typical serotonin-dopamine antagonist neuroleptics have 5-HT2 receptor antagonistic effect in addition to their dopamine blocking properties, and they have been reported to possess anti-aggressive behaviour (Connor et al. Exp. Opin. Ther. Patents. 1998, 8(4), 350-351).
Recently, evidence has also accumulated which support the rational for selective 5-HT2A antagonists as drugs capable of treating positive symptoms of psychosis (Leysen et al. Current Pharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion in CPNS Investigational Drugs 2000, 2(1), 22-24).
Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects at dopamine D4 and 5-HT2A receptors may have the further benefit of improved effect on positive and negative symptoms in schizophrenia, including depressive and anxiety symptoms.
Dopamine D4 ligands related to the compounds of the invention are known from WO 98/28293. The indane and dihydroindole derivatives disclosed herein have the general formula
wherein A is an indole and Y is a group completing an indane or a dihydroindole and the other substituents are as defined in the application.
Other dopamine D4 ligands, wherein the indane or dihydroindole is replaced by a pyrrolo[2,3-b]pyridine, a benzimidazole or a furo[2,3-b]pyridine, are described in WO 94/20497, WO 94/22839 and U.S. Pat. No. 5,700,802.
Most lipophilic drugs are mainly eliminated from the body through oxidative metabolism in the liver catalyzed by various cytochrome P450 isoenzymes.
The in vivo hepatic blood-clearance (CLb), considered to be the single most important pharmacokinetic parameter for the drugability of a drug (Bennet, L. The role of pharmacokinetics in the drug development process. Integration of pharmacokinetics, pharmacodynamics, and toxicology in rational drug development, Ed. A. Yacobi et al, Plenum Press, New York, 1993. P. 115-123), may in theory be estimated by calculation from the intrinsic clearance CLint, the hepatic blood flow (Q) and the free unbound fraction (fu) of the drug in the blood as CLb=(Q*fu*CLint)/(Q+fu*CLint). From this follows that drug substances with high measured values for CLint CLb will in vivo approximate to the hepatic blood flow (Q) resulting in low oral bioavailability and short half-lives.
The intrinsic clearance (CLint) is a theoretic measure for the metabolic capacity of a liver when there is no restrictions in blood supply of nutrients, co-factors etc. An in vitro approach for determining values for intrinsic clearance (CLint) in humans and animals using in vitro human and animal liver preparations, as described in detail by e.g. Obach, S. et al., The Prediction of Human Pharmacokinetic Parameters from Preclinical and In Vitro Metabolism Data. JPET. Vol. 283, Issue 1, 46-58, 1997, is widely implemented in the pharmaceutical industry and used for evaluating and optimizing drugability of potential drug candidates.
The oral bioavailability and systemic half-life of a compound in vivo are closely related to the blood-clearance, and compounds with higher oral bioavailability and longer half-lives in humans may be sought in a discovery program by optimization on intrinsic clearance (CLint), using human liver preparations, for values well below the average human liver blood flow of approximately 1.4 L/min.
One problem associated with some of the above-described compounds is that they possess poor oral bioavailability and that they are too rapidly cleared from the blood resulting in a very short half-live.